{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T05:22:29Z","timestamp":1769318549481,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health and Consumer Affairs FIS","award":["041665"],"award-info":[{"award-number":["041665"]}]},{"name":"Fundation La Caixa","award":["BN05-32-0"],"award-info":[{"award-number":["BN05-32-0"]}]},{"name":"Ministry of Education: Integrated Actions","award":["35201"],"award-info":[{"award-number":["35201"]}]},{"name":"Ramon y Cajal Programme","award":["2003"],"award-info":[{"award-number":["2003"]}]},{"name":"FIS","award":["PI052124"],"award-info":[{"award-number":["PI052124"]}]},{"name":"FIS","award":["CP04\/00132"],"award-info":[{"award-number":["CP04\/00132"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Calcium (Ca2+)signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca2+ homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca2+ dynamics associated with epileptiform activity. ER Ca2+ levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca2+ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca2+ oscillations. VPA induced a concentration-dependent release of Ca2+ from the ER, with an IC50 of approximately 17 \u00b5M. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP3). Pharmacological inhibition of InsP3 receptors (InsP3Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca2+ release, supporting a selective InsP3R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca2+ oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca2+ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP3R-mediated Ca2+ mobilization from the endoplasmic reticulum and identify ER Ca2+ release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca2+ signaling and excitability in epilepsy.<\/jats:p>","DOI":"10.3390\/ijms27031176","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T17:52:38Z","timestamp":1769190758000},"page":"1176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Valproic Acid Stimulates Release of Ca2+ from InsP3-Sensitive Ca2+ Stores"],"prefix":"10.3390","volume":"27","author":[{"given":"Ana","family":"Ruiz-Nu\u00f1o","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-6626","authenticated-orcid":false,"given":"Mar\u00eda F.","family":"Cano-Abad","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica, Hospital Universitario de la Princesa, 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1126\/science.285.5435.1870","article-title":"Long-term potentiation a decade of progress","volume":"285","author":"Malenka","year":"1999","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1139\/jpn.0703","article-title":"Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets","volume":"32","author":"Akimoto","year":"2007","journal-title":"J. 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